Of all the epidemiologic risk factors examined in schizophrena, familial/genetic factors have consistently been shown to be the most important. Despite major advances in psychiatric genetics, there has been a paucity of modern family/genetic studies of schizophrenia. This is a proposal for a comprehensive genetic epidemiologic study of schizophrenia in the West of Ireland. Its goal is to clarify in this population the nature of the familial/genetic and environmental risk factors for schizophrenia and the schizophrenia spectrum. To accomplish this goal, two inter-related studies are proposed. Pilot investigations have demonstrated the feasibility of both these studies. The first is a family study of first-degree relatives of 250 schizophrenic, 100 affectively ill and 150 matched control probands all of whom will be sampled from population based registries. Data analysis will include standard morbidity risk and symptom-based analyses as well as current and newly developed methods of complex segregation analysis. The second study will be to identify, study and establish cell-lines for DNA linkage analysis on 10 extended high-density schizophrenia pedigrees in Ireland. Results from the family study will aid in the analysis of the high density pedigrees. Specific aims of the project include: quantifying the role of familial factors in the etiology of schizophrenia in western Ireland, characterizing the schizophrenia spectrum at a syndrome, symptom and personality level, determining the specificity of this spectrum, detecting etiologic heterogeneity in schizophrenia and determining the mode of transmission of the liability to schizophrenia. Because of its cultural and racial homogeneity, absence of drug abuse, and large family size, the English-speaking, highly cooperative and relatively immobile population of the western Ireland represents a unique resource to further our understanding of the etiology of schizophrenia.